Intoxication with drugs that have general depressant effects on the central nervous system (especially alcohol and barbiturates) tend not to cause psychosis during use, and can actually decrease or lessen the impact of symptoms in some people. However, withdrawal from barbiturates and alcohol can be particularly dangerous, leading to psychosis or delirium and other, potentially lethal, withdrawal effects.

Some studies indicate that cannabis use may lower the threshold for psychosis, and thus help to trigger full-blown psychosis in some people.[30] Early studies have been criticized for failing to consider other drugs (such as LSD) that the participants may have used before or during the study, as well as other factors such as pre-existing ("comorbid") mental illness. However, more recent studies with better controls have still found a small increase in risk for psychosis in cannabis users.[31]

It is not clear whether this is a causal link, and it is possible that cannabis use only increases the chance of psychosis in people already predisposed to it; or that people with developing psychosis use cannabis to provide temporary relief of their mental discomfort. The fact that cannabis use has increased over the past few decades, whereas the rate of psychosis has not, suggests that a direct causal link is unlikely for all users.[32]